This invention relates to foods or drugs which are characterized by containing fructose-6-phosphate-2-kinase inhibitors, such as itaconic acid and its salts, as active ingredients, and which exert antiobesity, antidiabetic, and antilipemic effects due to the existence of inhibitors that function to suppress the glycolytic pathway and the activity of phosphofructokinase, a regulatory enzyme of the glycolytic pathway. The invention also relates to a method for preparing these foods or drugs.
Obesity tends to cause such complications as hypertension, abnormal glucose tolerance, or hyperlipidemia, and is considered to be a risk factor in diseases such as ischemic heart disease, cerebral apoplexy, and diabetes. From the point of view of preventing such diseases, prevention of obesity is of vital importance.
Obesity refers to an excessive accumulation of fat in the body. This state occurs when regulatory function on energy balance becomes impaired, or when intake of energy exceeds consumption of energy over a long period beyond the range tolerable for the regulatory function. Thus, obesity is improved by rectifying the impaired regulatory function to normal, or by forcibly increasing energy consumption (exercising) and restricting energy intake (dieting), to create an energy deficient state whereby fat in the body is consumed. However, the conventionally adopted measures of regular exercise and controlled dieting in a busy daily life are often not adhered to by obesity sufferers. Therefore, a number of persons classified as obese tends to be increasing.
Impairment of the regulation of energy balance in the body for the reasons as outlined abovexe2x80x94excessive energy intake versus consumption over a protracted periodxe2x80x94can also lead to the development diseases such as diabetes and hyperlipidemia. As antidiabetic agents there are commercially available inhibitors of carbohydrate degradation enzymes, which inhibit the degradation or absorption of carbohydrates. However, administration of these enzymes can cause adverse reactions, such as hypoglycemia, loose stools or diarrhea, and therefore are required to be administered under management by physicians. Clofibrate-derived drugs and nicotinate drugs are used as antilipemic agents, but again, these drugs are required to be administered under management by physicians.
In the body, carbohydrates taken in from foods are first used for glycogen synthesis in the liver and muscles. Accumulated glycogen in the liver is used by the body to prevent decreases in fasting blood glucose. Excessive carbohydrate is metabolized by the hepatic glycolytic pathway and converted into acetyl-CoA. It is then available for use partially as an energy source, but is mostly utilized in the synthesis of fatty acids or lipids such as cholesterol.
The regulatory enzyme for glycolytic pathway metabolism in the liver is phosphofructokinase (PFK). This enzyme is inhibited by adenosine triphosphate (ATP), citric acid, and phosphoenolpyruvic acid (PEP), and activated by adenosine monophosphate (AMP) and fructose 6-phosphate (F6P). However, changes in the concentrations of these regulatory factors in the liver, unlike those in muscles, are not sufficient to account for changes in the activity of PFK. Thus, a problem existed in finding a satisfactory explanation of the regulation of hepatic PFK activity. Under these circumstances, a search for new regulatory factors for PFK was conducted, and in 1980, fructose 2,6-bisphosphate (F26BP) was isolated as the most potent activating factor (E. Furuya and K. Ueda, Proc., Natl. Acad. Sci. U.S., Vol. 77, 5861-5864, 1980; E. Van Schaftingen et al., Biochem. J., Vol. 192, 887-895 and 897-901, 1980).
F26BP is said to be a regulatory factor, rather than a mere activating factor for PFK because the intracellular concentration of F26BP rapidly changes with insulin or glucagon. F26BP is synthesized from F6P by the action of fructose-6-phosphate-2-kinase (F6P2kinase). F26BP is converted to F6P by the action of fructose 2,6-bisphosphatase (F26pase). These two enzyme activities are shouldered by a single enzyme protein (bifunctional enzyme). Dephosphorylation of this enzyme protein promotes activity of F6P2kinase, while phosphorylation of the enzyme protein promotes activity of F26Pase. Following the ingestion of carbohydrate, insulin is secreted by the pancreas. Protein phosphatase activated by insulin dephosphorylates the bifunctional enzyme to activate F6P2kinase, thereby increasing the concentration of F26BP. As a result, PFK is activated to promote metabolism of the glycolytic pathway. In a fasting state, on the other hand, the bifunctional enzyme is phosphorylated by the action of glucagon to activate F26Pase to decrease the concentration of F26BP. Thus, the activity of PFK declines, suppressing the metabolism of the glycolytic pathway (E. Furuya et al., Pro., Natl. Acad. Sci. U.S., Vol. 79, 325-329, 1982).
As described above, the fructose 6-phosphate-2-kinase:fructose 2,6-bisphosphatase bifunctional enzyme (F6P2kinase:F26Pase) undergoes regulation by phosphorylation with glucagon-activated cAMP-dependent protein kinase, and dephosphorylation with insulin-activated protein phosphatase. Its enzyme activities are also known to be affected by glycerol 3-phosphate (Glycerol 3-P), phosphoenolpyruvic acid (PEP), 3-phosphoglycerate (3-P-glycerate), and 2-phosphoglycerate (2-P-glycerate). These regulatory factors have been reported to inhibit F6P2kinase, promote F26Pase activity, and also promote phosphorylation of F6P2kinase:F26Pase (E. Van Schaftingen, Adv. Enzymol. Vol. 59, 315-395, 1987).
In view of the foregoing, there has been a demand for the development of foods, drinks, or drugs, which exert safely an antiobesity, antidiabetic, and antilipemic effect without involving distress.
The inventors of the present invention directed their attention to the regulation of the glycolytic pathway metabolism as a way of decreasing energy intake without reducing food intake. They searched for substances among food components active in inhibiting glycolytic pathway metabolic enzymes, which can be utilized safely and conveniently. As a result, they identified itaconic acid as one of the fructose 6-phosphate-2-kinase inhibitors which suppresses the activity of phosphofructokinase, a regulatory enzyme for glycolytic pathway metabolism. In animals administered itaconic acid, weight gain was suppressed, blood glucose and plasma triglycerides were controlled to low values, and rapid rises in blood glucose following the ingestion of food were suppressed. Moreover, in streptozotocin-induced diabetes rats elevation of blood glucose was suppressed with itaconic acid. Thus, itaconic acid was confirmed to have not only an obesity preventing effect, but also an antidiabetic effect and an antilipemic effect. Based on these findings, the inventors accomplished the present invention. Itaconic acid was notified as being included in the List of Food Additives in 1996 by the Director-General, Environmental Health Bureau, Ministry of Health and Welfare, Japan, but its use was restricted to an acidulant.